[1] The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology.
The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH.
[9] GnRH neurons are derived from the olfactory placode and migrate into the central nervous system (CNS) during embryonic development.
[9] Embryonic migration can be affected by several gene mutations including but not limited to, KAL1, fibroblast growth factor (FGF8), sex determining region Y-Box 10 (SOX10), GNRHR, GNRH1 and KISS1R.
[8] Inactivating mutations in the genes encoding GNRH1 or its receptor will result in the failure of the HPG axis and give rise to normosmic CHH.
[2] This is because KISS1 is the mediator for the feedback loop in the HPG axis allowing low levels of sex steroid to stimulate GnRH secretion from the hypothalamus.
[10] Congenital hypogonadotropic hypogonadism, CHH, is a genetically, as well as clinically, heterogenous disorder stemming from over 25 causal genes identified to date,[11] with cases reported as being X-linked, recessive and autosomally inherited.
[4] There are many causes of AHH, mostly due to structural lesions or functional abnormalities involving the HPG axis such as sarcoidosis, lymphocytic hypophysitis, pituitary adenomas, craniopharyngiomas and other CNS tumours.
There is evidence to suggest indirect inhibition of GnRH neurons mediated by other neurotransmitters such as dopamine, opioid, neuropeptide Y and γ-aminobutyric acid.
[14] Chronic treatment with supraphysiological doses of glucocorticoids results in a marked decrease in testosterone without an increase of LH levels, suggestive of a central mechanism of induced HH.
Clinical presentations of CHH involve an absence of puberty by 18 years of age, poorly developed secondary sexual characteristics, or infertility.
[4] Another clinical sign of CHH, more specifically Kallmann syndrome, is a lack of a sense of smell due to the altered migration of GnRH neurons on the olfactory placode.
[16] The goal for HH therapy is to induce pubertal development, sexual function, fertility, bone health, and psychological wellbeing.
In the male, hCG stimulates Leydig cells to produce testosterone so that plasma and testicular levels increase.
[citation needed] In up to 10–20% of cases, patients can exhibit sustained fertility and steroid production after therapy, resulting in hypogonadotropic hypogonadism reversal.